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The primary output neurons from the cerebellum are the Purkinje neurons that transmit inhibitory responses to deep cerebellar nuclei through their myelinated axons. Altered morphological organization and electrical properties of the Purkinje axons lead to detrimental changes in locomotor activity often leading to cerebellar ataxias. Two cytoskeletal scaffolding proteins Band 4.1B (4.1B) and Whirlin (Whrn) have been previously shown to play independent roles in axonal domain organization and maintenance in myelinated axons in the spinal cord and sciatic nerves. Immunoblot analysis had indicated cerebellar expression for both 4.1B and Whrn; however, their subcellular localization and cerebellum\u2010specific functions have not been characterized. Using <jats:italic>4<\/jats:italic>.<jats:italic>1B<\/jats:italic> and <jats:italic>Whrn<\/jats:italic> single and double mutant animals, we show that both proteins are expressed in common cellular compartments of the cerebellum and play cooperative roles in preservation of the integrity of Purkinje neuron myelinated axons. We demonstrate that both 4.1B and Whrn are required for the maintenance of axonal ultrastructure and health. Loss of 4.1B and Whrn leads to axonal transport defects manifested by formation of swellings containing cytoskeletal components, membranous organelles, and vesicles. Moreover, ablation of both proteins progressively affects cerebellar function with impairment in locomotor performance detected by altered gait parameters. Together, our data indicate that 4.1B and Whrn are required for maintaining proper axonal cytoskeletal organization and axonal domains, which is necessary for cerebellum\u2010controlled fine motor coordination.<\/jats:p>","DOI":"10.1002\/jnr.24352","type":"journal-article","created":{"date-parts":[[2018,11,17]],"date-time":"2018-11-17T09:40:46Z","timestamp":1542447646000},"page":"313-331","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Ablation of cytoskeletal scaffolding proteins, Band 4.1B and Whirlin, leads to cerebellar purkinje axon pathology and motor dysfunction"],"prefix":"10.1002","volume":"97","author":[{"given":"Julia","family":"Saifetiarova","sequence":"first","affiliation":[{"name":"Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, Long School of Medicine University of Texas Health Science Center San Antonio Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0989-1498","authenticated-orcid":false,"given":"Manzoor A.","family":"Bhat","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, Long School of Medicine University of Texas Health Science Center San Antonio Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,11,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1868"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2990.1999.00167.x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2007.09.015"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3181da84db"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00294-X"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00296-3"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.1093\/hmg\/11.23.2837","article-title":"Charcot\u2010Marie\u2010Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport","volume":"11","author":"Brownlees J.","year":"2002","journal-title":"Human Molecular Genetics"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1015-11.2011"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5602-11.2012"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1527-05.2005"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1089\/neu.1988.5.47"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0025043"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2736(82)90281-4"},{"key":"e_1_2_10_15_1","first-page":"58","article-title":"Structure, function, and molecular genetics of erythroid membrane skeletal protein 4.1 in normal and abnormal red blood cells","volume":"30","author":"Conboy J. 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